Preparation of aminoindane compounds



Eatenteci jan.

PREPARATION OF AMINOINDANE COMPOUNDS MiltonJ. Allen, Baltimoradtidt, assignor to the United States of America as represicnted by the Administrator of the Federal Security Agency No Drawing. Application November 5, 1948, Serial No. 58,632

4 Claims.

(Granted under the act of March 3, 1883, as amended April 30, 1928 370 O. G. 757) The invention described herein may be manufactured and used by .or for the Government of the United States for governmental purposes without the payment to me of any royalty thereon in accordance with the provisions of the act of April 30, 1928 (ch.-460, 45 Stat. L. 467).

This invention relates to the production-of new chemical compounds and to processes therefor. More particularly, this invention relates to the production of aminoindanes and aminoindenes from bis-aminophenyl alkyl glycols. This' invention also relates to the production of valuable byproducts during the production of the above- ;mentioned indanes.

Heretofore, it was known that certain hydroxy =indenes, closed ring analogs of stilbestrol, and rcertain hydroxy indanes, closed ring analogs of -the hexestrol type, possessed estrogenic proper- ;ties. It has been found that certain amino- -phenyl alkyl 'indeneamines and indaneamines possess estrogenic activity. These can be prepared in a simpleofashion from biseaminophenyl :alkyl 'ethyleneuglycols. During the course of the preparation, there is usually formed an appre- (ciable quantity of valuableoxocompounds suit- ;able for -1f.urther conversion into substituted :s'tilbenes. -Accordingly; this inven'tlon has for 'an objec't the production of -2-' (p-aminophenyl) -'-3-methyllG-a'minoindene and 2-'(p-aminophenyl) -'3-'-methyl-fi-"aminoindane' and their corresponding hydrochlorides. A further objectof this invention is to 'p'roduce the above indane and indene compounds from bis-(p-aminophenyl) methyl ethylene glycol 'dihydrochlori'de. Another object is to produce as a va uable by-pro'duct, gammaoxo-beta, gamma (di p aminophenyll-betamethyl propane. *Other objects will be apparent or will appear hereinafter as the ensuing de- .scrintion proceeds.

Theforegoing objects are accomplishedin accordance with this invention wherein bis-(par ninophenyl) methyl ethy ene glycol dihydrochloridels subjected 'to a dehydration reaction to "yi ld "2-'(p-aminopheny1) -3-methyl-6-indene- "amino 'st lhene' 'com ounds'as descri ed in my co-pendln a p i at on. S rial No. 58,631, filed on concurrent date herewith.

While this invention is not to be limited by any theoretical explanation, the following equations illustrate. a reaction mechanism which agrees with data now on hand:

Bis-(p-aminophenyl) methyl ethylene glycol dihydrochloride CH3 CH3 its (511 Dehydration Gamma-oXo-beta, gammadi-p-aminophenyl) beta-methyl pitqpa dil do p h ride hydrochloride NH H- l Hydrogenation -(pa i op ll 3methyk ammo n dihydrochloride @mm-nm Aqueous alkali '2- (p-aminophenyll -3-methyl-6 aminoindane The starting material. for the hereindescribed process, bis-(p-aminophenyl) .methyl ethylene glycol dihydrochloride is. prepared fromp-aminoacetophenone by electrolytic bimolecular reduction :as described inmy co-pending application,

Serial Number 58,630, filed on concurrent date herewith.

The dehydration of this invention is carriedout by subjecting'the aforesaid glycol compoundito'.

dihydrochloride with to 300 parts by. weight of --water and 50 to partsby weight of concentrated hydrochloric acid (37%), results in a good dehydration of the glycol compound. As the quantity of water is increased a larger proportion of the glycol compound is converted into gamma-oxo-beta, gamma di(p-amino-phcnyl) beta methyl propane dihydrochloride and a smaller proportion of Z-(p-aminophenyl) -3- m e t h y 1 6 indeneamine dihydrochloride is formed. With a higher proportion of concentrated hydrochloric acid, decomposition increases with concurrent formation of tarry byproducts.

Heating the mixture of the said glycol compound, water and hydrochloric acid to boiling, under reflux is a preferred method or way to carry out the dehydrating step. In general, one may simply heat the reaction mixture in an ordinary glass reaction flask equipped with a reflux condenser to condense and return evolved vapors to the reaction mixture. As is known to those skilled in the art, this step is generally described as refluxing the reaction mixture. The refluxing is continued until the desired 2- (p-aminophenyl) 3 methyI-G-indeneamine dihydrochloride is formed. Thereupon, there is preferably incorporated an additional quantity of concentrated hydrochloric acid and the reaction mixture is chilled in a refrigerator overnight or for several hours. This accomplishes a salting out of the crystalline product which under these conditions crystallizes out of the reaction mixture. The crude product in crystalline form is filtered from the cool reaction mixture and preferably recrystallized by dissolving the crude product in a minimum amount of water, filtering the solution, and then adding an equal quantity of hydrochloric acid to salt out the crystals again. The purified product is recovered by fi.tering the crystals from the hydrochloric acid solution. The free base of the indene compound is prepared from the dihydrochloride by dissolving the crystalline indene compound salt in water and neutralizing with a dilute aqueous alkali such as, for example, ammonium hydroxide solution, sodium hydroxide solution, or potassium hydroxide solution. Recrystallization of the free amine from methanol results in the compound Z-(p-aminophenyl)-3-methyl-6-aminoindene, melting at 168-169 C. with decomposition.

The original mother liquor from the dehydration is saved and evaporated to a very small volume, an equal quantity of absolute ethanol is added and chilled to induce crystallization. The crystalline gamma oxo beta, gamma- (di-paminophenyl) -beta methyl propane dihydrochloride is separated by filtration. This compound melts with decomposition at 270-273 C. As described in my co-pending application, Serial No. 58,631, filed on concurrent date herewith, the x0 compound can readily be converted into estrogenic aminostllbene compounds.

After separation of the formed Z-(p-aminophenyl)-3-methylindeneamine dihydrochloride, the said indeneamine compound is hydrogenated to the corresponding indane compound by treating a solution thereof with catalytic or nascent hydrogen. The indene double bond is thereupon saturated to give the indane compound. A suitable way of accomplishing this hydrogenation may be by treatment with gaseous hydrogen in the presence of nickel on kieselguhr, Raney nickel, or the like, but preferably, the indene double bond is saturated by treating the indeneamine dihydrochloride salt with anhydrous normal propanol and sodium metal to yield Z-(paminophenyl) -3-methy1 6 aminoindane. In

' 4 general, the indeneamine salt is treated with, per part thereof, about 2 to 4 parts by weight of sodium metal and about 40 to 60 parts by weight of normal propanol. After completion of the reaction, which is stimulated by heating under refiux conditions, an excess of water is added to the reaction mixture and the residual alcohol evaporated oil. The aqueous mixture is chilled, whereupon the aminoindane compound is precipitated in the form of crystals. The aqueous mother liquor, containing sodium chloride and sodium hydroxide, is removed by filtration, and the aminoindane compound is recrystallized from a suitable solvent, e. g., methanol, to yield a purified aminoindane compound. The product, 2- (p-aminophenyl)-3-methyl-6-aminoindane has a melting point of l62163 C.

The following illustrative examples show how the invention may be carried out, but it is not limited thereto:

Example I.Preparation of Z-(p-aminophenyl) 3 -methyZ-6-amin,oindene 28.7 grams of bis-(p-aminophenyl) methyl ethylene glycol dihydrochloride are refluxed for one and one-half hours with 100 ml. concentrated HCl and 200 ml. H2O. At the end of this period an additional 100 ml. conc. HCl are added and- Example II.Preparation of 2- (p-aminophenyl) 3-methyZ-6-amz'noindane 1.2 grams of indene dihydrochloride are refiuxed with 60 ml. n-propyl alcohol to which is added portionwise over a period of one hour 3.6 grams of sodium. After all the sodium is added, the mixture is allowed to reflux for an additional one hour. An excess of water is added and the alcohol evaporated. The aqueous mixture is chilled and indane filtered. After washing and recrystallization from methanol a compound,

M. P. 162163 C. is obtained in 95% yield.

Both the produced aminoindene and amino-- indane compounds possess valuable estrogenic properties. Therefore, it will be apparent that new and valuable chemical compounds have been produced in accordance with this invention by a simple process yielding also a valuable by-product.

While the invention has been particularly described with reference to the production of methyl substituted aminoindenes and aminoindanes from the methyl substituted glycols, it will be apparent that other substituted indenes such as, for example, ethyl, propyl and the like, may be prepared from the corresponding substituted glycols by the process of this invention.

Since many apparently differing embodiments of this invention will occur to one skilled in the art, various changes can be made therein without departing from the spirit and scope thereof.

What is claimed is:

1. An estrogenic compound selected from the group consisting of Z-(p-aminophenyD-S- methyl-fi-aminoindene, and 2-(p-amin0pheny1).-

3-methy1-6-aminoindane and the hydrochlorides thereof.

2. 2 (p aminophenyl) 3 methyl 6 aminoindene.

3. 2 (p aminophenyl) 3 methyl 6 aminoindane.

4. A process for the production of 2-(p-aminophenyl)-3-methyl-6-aminoindane which comprises heating to boiling a mixture of about 50 to 150 parts by weight concentrated hydrochloric acid, 100 to 300 parts by weight of water, and 10 to 50 parts by weight of bis-(p-aminophenyl) methyl ethlene glycol dihydrochloride, and continuing said heating while condensing evolved vapors and returning condensate to said mixture until 2- (p-aminophenyl) -3-methyl-6-indene- IVIILTON J. ALLEN.

REFERENCES CITED The following references are of record in the file of this patent:

Bergmann: Ber. deut. chem, vol. 65, pp. 109-122 (1932).

Mee: Richters Organic Chemistry (Elsevier Pub. 00., Inc., N. Y.), vol. III, page 591 (1946). 

1. AN ESTROGENIC COMPOUND SELECTED FROM THE GROUP CONSISTING OF 2-(P-AMINOPHENYL)-3METHYL-6-AMINOINDENE, AND 2-(P-AMINOPHENYL)-33-METHYL-6-AMINOINDANE AND THE HYDROCHLORIDES THEREOF. 